In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy

Abstract

Monoclonal antibodies targeting the immune checkpoint Programmed Death-1 (aPD-1 mAbs) have demonstrated impressive benefits for the treatment of some cancers; yet, these drugs are not always effective and we still have a limited understanding of the mechanisms that contribute to their efficacy or lack thereof. Here we employed in vivo imaging to uncover the fate and activity of aPD-1 mAbs in real-time and at subcellular resolution in mice. We show that aPD-1 mAbs effectively bind PD-1+ tumor-infiltrating CD8+ T cells at early time-points after administration. However, this engagement is transient, as aPD-1 mAbs are captured within minutes from the T cell surface by PD-1− tumor-associated macrophages. We further show that macrophage accrual of aPD-1 mAbs depends both on the drug’s Fc domain glycan and on Fcγ-receptors (FcγRs) expressed by host myeloid cells, and extend these findings to the human setting. Finally, we demonstrate that in vivo blockade of FcγRs prior to aPD-1 mAb administration substantially prolongs aPD-1 mAb binding to tumor-infiltrating CD8+ T cells and enhances immunotherapy-induced tumor regression in mice. These investigations yield new insight into aPD-1 target engagement in vivo and identify specific Fc : FcγR interactions that can be modulated to improve checkpoint blockade therapy.

Molecular mobility and activity in an intravital imaging setting – implications for cancer progression and targeting

“…Images in Bi adapted from Beerling et al (2016) under https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode. Images in C, E,F adapted from Arlauckas et al (2017), , Vennin et al (2017), respectively, with permission from AAAS. Image in D adapted from Weigelin et al (2015).…”

“…For example, treatment of colorectal cancer, lung cancer and melanoma xenograft models with fluorescently labelled anti-PD1 (PD1 is also known as PDCD1) showed that TAMs take up anti-PD1 from the surface of cytotoxic T-cells (CTLs), which is mediated by FCγ receptors ( Fig. 2C; Arlauckas et al, 2017). Based on these observations, combination treatments consisting of FCγR inhibition and anti-PD1 antibodies were tested in vivo, which improved immunotherapy performance by extending the time anti-PD1 localised to CTLs (Arlauckas et al, 2017).…”

“…2C; Arlauckas et al, 2017). Based on these observations, combination treatments consisting of FCγR inhibition and anti-PD1 antibodies were tested in vivo, which improved immunotherapy performance by extending the time anti-PD1 localised to CTLs (Arlauckas et al, 2017). Similarly, longitudinal IVM of interactions between cancer and immune cells revealed the formation of an immunosuppressive 'ring' of Tregulatory cells around the tumour that can inhibit CTL efficacy (Qi et al, 2016).…”

Immunotherapy and Combination Strategies in Pancreatic Cancer: Current Status and Emerging Trends

“…Local irradiation of tumor cells induces release of tumor antigens, thereby facilitating specific immune responses and causing severe damage to the tumor vasculature [46]. Following irradiation, TAMs as the primary tumor-resident population of phagocytes promote early endothelial regrowth and restoration of the vasculature by secreting vascular endothelial growth factor and other proangiogenic mediators [47].…”

The application and mechanism of PD pathway blockade for cancer therapy

“…They found that PD-1 still remains on the T-cell surface after PD-1 antibody removal, but the PD-1 molecules bind the new antibody. Therefore, uncovering the mechanism that mAbs interacti with host cells is an ongoing challenge and is very important to overcome the immunosuppressive tumour microenvironment 68. Above all, different kinds of therapeutic agents enhancing antitumour T cells and reversing the immunosuppressive tumour-microenvironment may be crucial in improving the antitumour immune response.…”